MKP-1 modulates ubiquitination/phosphorylation of TLR signaling.
MKP-1 modulates ubiquitination/phosphorylation of TLR signaling.
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DOI：
10.26508/lsa.202101137
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发表时间：
2021-12
影响因子：
4.4
通讯作者：
Samavati L
中科院分区：
文献类型：
--
作者：
Talreja J;Bauerfeld C;Wang X;Hafner M;Liu Y;Samavati L
MKP-1是一种双特异性磷酸酶，已知可使p38和JNK去磷酸化。这项研究首次表明，MKP-1调节泛素连接酶（TRAF 6）和去泛素化酶以及上游TLR信号分子的景观。泛素化和磷酸化是可逆的蛋白质翻译后修饰，调节生理和病理过程。MAPK磷酸酶（MKP）-1调节先天性和适应性免疫。MKP-1的多方面作用归因于p38和JNK MAPK的去磷酸化。我们发现，MKP-1的缺乏调节泛素连接酶和去泛素酶（DUBs）的景观。MKP-1−/−显示了几种DUB的异常调节，以及MAPK上游参与IL-1/TLR信号传导的蛋白质和基因的表达增加，包括IL-1 R1，IRAK 1，TRAF 6，磷酸化的TAK 1，以及TRAF 6上K63多聚泛素化的增加。TRAF 6上K63多聚泛素化的增加与A20磷酸化形式的增强有关。在丰富的DUB中，泛素特异性蛋白酶-13（USP 13），其切割客户蛋白上的聚泛素链，在鼠MKP-1缺陷型BMDM中显著增强。在BMDM中，USP 13的抑制剂降低了K63对TRAF 6、TAK 1磷酸化、IL-1β和TNF-α诱导的多聚泛素化，以响应LPS。我们的数据首次表明，MKP-1通过调节特定DUB来调节TRAF 6的连接酶活性。
MKP-1 is a dual-specific phosphatase best known to dephosphorylate p38 and JNK. This study shows for the first time that MKP-1 modulates the landscape of ubiquitin ligases (TRAF6) and deubiquitinase enzymes, as well as upstream TLR signaling molecules. Ubiquitination and phosphorylation are reversible posttranslational protein modifications regulating physiological and pathological processes. MAPK phosphatase (MKP)-1 regulates innate and adaptive immunity. The multifaceted roles of MKP-1 were attributed to dephosphorylation of p38 and JNK MAPKs. We show that the lack of MKP-1 modulates the landscape of ubiquitin ligases and deubiquitinase enzymes (DUBs). MKP-1−/− showed an aberrant regulation of several DUBs and increased expression of proteins and genes involved in IL-1/TLR signaling upstream of MAPK, including IL-1R1, IRAK1, TRAF6, phosphorylated TAK1, and an increased K63 polyubiquitination on TRAF6. Increased K63 polyubiquitination on TRAF6 was associated with an enhanced phosphorylated form of A20. Among abundant DUBs, ubiquitin-specific protease-13 (USP13), which cleaves polyubiquitin-chains on client proteins, was substantially enhanced in murine MKP-1–deficient BMDMs. An inhibitor of USP13 decreased the K63 polyubiquitination on TRAF6, TAK1 phosphorylation, IL-1β, and TNF-α induction in response to LPS in BMDMs. Our data show for the first time that MKP-1 modulates the ligase activity of TRAF6 through modulation of specific DUBs.